Neurogranin is a neuron-specific protein that is enriched in the hippocampus and cortex. Neurogranin has been implicated in several neurological disorders, such as Alzheimer's disease, schizophrenia, aging, hypothyroidism and stress, and its levels correlate with memory performance. On a molecular level, neurogranin binds to calmodulin, a key regulator of synaptic plasticity, only in absence of Calcium. Synaptic plasticity is the ability of synapses to change their strength. The two most commonly studied forms of synaptic plasticity are long term potentiation (LTP) and long term depression (LTD). In CA1 hippocampal synapses, both forms of synaptic plasticity are dependent on NMDA receptor activation and coexist in a tight balance that is dependent on calmodulin availability. Thus, through its regulation of CaM availability, neurogranin may play an important role in synaptic plasticity. Indeed, two independent genetic studies of Neurogranin knockout highlight such importance in plasticity and memory. However, these two studies had opposite results when looking at synaptic plasticity induction. The aim of this proposal is to define the molecular role of neurogranin in synaptic plasticity. This will be achieved by integrating a combination of electrophysiology, molecular biology and imaging techniques. We propose that Ng controls the synaptic plasticity balance through its regulation of CaM availability. The first specific aim will assess the role of neurogranin in LTP and LTD bidirectional regulation. In the second specific aim, we will study the localization and dynamics of neurogranin within the spine during synaptic plasticity. Finally, we will test the regulation and interaction between Ng and CaM. Success in the proposed experiments will elucidate one of the fundamental mechanisms that may control the synaptic plasticity balance and will enable us to better understand the alterations that may contribute to the pathophysiology of many neurological disorders. PUBLIC HEALTH RELEVANCE Neurogranin has been implicated in several neurological disorders, such as Alzheimer's disease, schizophrenia, hypothyroidism, stress and aging. Neurogranin plays a significant role in synaptic plasticity and memory, and its down regulation may result in cognitive dysfunction. We hypothesize that neurogranin controls the synaptic plasticity balance, through its regulation of calmodulin availability. Thus we propose to study the role of neurogranin in synaptic plasticity, which, we believe, will enable us to better understand the molecular alterations that may contribute to the pathophysiology of many neurological diseases.